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1.
Toxicol Appl Pharmacol ; 410: 115341, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33242555

RESUMEN

Andrographolide (AND) is the major diterpenoid in A. paniculata with wide clinical application and has been shown to be a potent anti-inflammatory agent. Gout is the leading inflammatory disease of the joints, and the deposition of urate in the articular cavity attracts immune cells that release inflammatory cytokines. Monosodium urate (MSU) is known to be one of the activators of the NLRP3 (NLR family pyrin domain containing 3) inflammasome. After activation, the NLRP3 inflammasome releases interleukin-1ß (IL-1ß), which causes the development of many inflammatory diseases. The aim of the present study was to investigate whether AND attenuates the release of IL-1ß mediated by the NLRP3 inflammasome. The effects of AND were studied in bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS) and MSU and in mice with MSU-induced joint inflammation. AND suppressed MSU phagocytosis dose-dependently and markedly inhibited LPS- and MSU-induced IL-1ß release in BMDMs. Moreover, AND pretreatment inhibited the LPS-induced NLRP3 inflammasome priming stage by inhibiting the IKK/NFκB signaling pathway, which resulted in decreased protein expression of NLRP3 and proIL-1ß. AND induced HO-1 protein expression in a dose-dependent manner and attenuated MSU-induced ROS generation. Silencing HO-1 mitigated AND inhibition of LPS/MSU-induced IL-1ß release in J774A.1 cells. In addition, AND decreased MSU-mediated ASC binding to NLRP3. Oral administration of AND attenuated MSU-induced monocyte infiltration in mouse knee joints. These results suggest that the working mechanisms by which AND down-regulates MSU-induced joint inflammation might be via HO-1 induction and attenuation of ROS-mediated NLRP3 inflammasome assembly and subsequent IL-1ß release.


Asunto(s)
Diterpenos/farmacología , Interleucina-1beta/antagonistas & inhibidores , Articulación de la Rodilla/efectos de los fármacos , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Ácido Úrico/toxicidad , Animales , Antiinflamatorios/farmacología , Antioxidantes/toxicidad , Línea Celular , Células Cultivadas , Humanos , Interleucina-1beta/metabolismo , Articulación de la Rodilla/metabolismo , Articulación de la Rodilla/patología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo
2.
Toxicol Appl Pharmacol ; 393: 114941, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32126212

RESUMEN

Incidence of nonalcoholic fatty liver disease is increasing worldwide. Activation of the NLRP3 inflammasome is central to the development of diet-induced nonalcoholic steatohepatitis (NASH). We investigated whether benzyl isothiocyanate (BITC) ameliorates diet-induced NASH and the mechanisms involved. C57BL/6 J mice fed a high-fat diet containing cholesterol and cholic acid (HFCCD) and Kupffer cells stimulated with LPS and cholesterol crystals (CC) were studied. LPS/CC increased the expression of the active form of caspase 1 (p20) and the secretion of IL-1ß by Kupffer cells, and these changes were reversed by MCC950, an NLRP3 inflammasome inhibitor. LPS/CC-induced NLRP3 inflammasome activation and IL-1ß production were dose-dependently attenuated by BITC. BITC decreased cathepsin B release from lysosomes and binding to NLRP3 induced by LPS/CC. Compared with a normal diet, the HFCCD increased serum levels of ALT, AST, total cholesterol, and IL-1ß and hepatic contents of triglycerides and total cholesterol. BITC administration (0.1% in diet) reversed the increase in AST and hepatic triglycerides in the HFCCD group. Moreover, BITC suppressed lipid accumulation, macrophage infiltration, fibrosis, crown-like structure formation, and p20 caspase 1 and p17 IL-1ß expression in liver in the HFCCD group. These results suggest that BITC ameliorates HFCCD-induced steatohepatitis by inhibiting the activation of NLRP3 inflammasome in Kupffer cells and may protect against diet-induced NASH.


Asunto(s)
Colesterol en la Dieta/efectos adversos , Colesterol/química , Ácido Cólico/efectos adversos , Dieta Alta en Grasa/efectos adversos , Inflamasomas/efectos de los fármacos , Isotiocianatos/uso terapéutico , Macrófagos del Hígado/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Colesterol/sangre , Relación Dosis-Respuesta a Droga , Interleucina-1beta/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Pruebas de Función Hepática , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Triglicéridos/metabolismo
3.
Molecules ; 24(18)2019 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-31547327

RESUMEN

Previous studies have revealed the anti-inflammatory and neuroprotective properties of Hericium erinaceus extracts, including the fact that the active ingredient erinacine C (EC) can induce the synthesis of nerve growth factor. However, there is limited research on the use and mechanisms of action of EC in treating neuroinflammation. Hence, in this study, the inflammatory responses of human BV2 microglial cells induced by LPS were used to establish a model to assess the anti-neuroinflammatory efficacy of EC and to clarify its possible mechanisms of action. The results showed that EC was able to reduce the levels of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) proteins produced by LPS-induced BV2 cells, in addition to inhibiting the expression of NF-κB and phosphorylation of IκBα (p-IκBα) proteins. Moreover, EC was found to inhibit the Kelch-like ECH-associated protein 1 (Keap1) protein, and to enhance the nuclear transcription factor erythroid 2-related factor (Nrf2) and the expression of the heme oxygenase-1 (HO-1) protein. Taken together, these data suggest that the mechanism of action of EC involves the inhibition of IκB, p-IκBα, and iNOS expressions and the activation of the Nrf2/HO-1 pathway.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Diterpenos/farmacología , Microglía/efectos de los fármacos , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Proteínas de la Membrana/metabolismo , Ratones , Microglía/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
4.
Toxicol Appl Pharmacol ; 359: 82-90, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30248417

RESUMEN

Obesity is highly correlated with several metabolic disorders. Adipocyte differentiation is a key process in determining obesogenesis. 14-Deoxy-11,12-didehydroandrographolide (deAND) is a diterpenoid rich in Andrographis paniculata (Burm.f.) Nees., a herbal medicine commonly used to treat colds, infections, and liver diseases. We investigated whether deAND inhibits the adipogenesis of 3T3-L1 cells and the underlying mechanisms. We found that deAND (0-15 µM) dose-dependently inhibits the mRNA and protein expression of peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein 1c, fatty acid synthase, and stearoyl-CoA desaturase-1. Cellular lipid accumulation was decreased by deAND, and the early phase of adipocyte differentiation was critical for this inhibition. Immunoblotting revealed that deAND attenuated differentiation medium-induced protein kinase A (PKA) and cAMP response element-binding protein (CREB) activation, which leads to down-regulating C/EBPß transcription. Moreover, deAND inhibited ERK- and GSK3ß-mediated C/EBPß transcriptional activity. Flow cytometry analysis showed that deAND impaired the progression of mitotic clonal expansion (MCE) by arresting the cell cycle at the G0/G1 phase, while the expression of cyclin D1, cyclin E, CDK6, and CDK2 was attenuated. deAND increased the phosphorylation of AMPK and raptor, an mTOR-interacting partner, which inhibited the mTOR-driven phosphorylation of P70S6K and eukaryotic translation initiation factor 4E binding protein. In the presence of compound C, deAND modulation of AMPK-mTOR signaling and inhibition of cell cycle regulator expression were reversed. Our results reveal that the anti-adipogenic effect of deAND is likely through inhibition of the PKA-CREB-C/EBPß and AMPK/mTOR pathways, which leads to down-regulating C/EBPß-driven lipogenic protein expression and halting MCE progression.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Proteína beta Potenciadora de Unión a CCAAT/antagonistas & inhibidores , Diterpenos/farmacología , Mitosis/efectos de los fármacos , Células 3T3-L1 , Activación Metabólica/efectos de los fármacos , Andrographis/química , Animales , Células Clonales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Transducción de Señal/efectos de los fármacos , Células Madre/efectos de los fármacos
5.
Nutr Cancer ; 70(1): 116-124, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29111778

RESUMEN

Carotenoids have been shown to exhibit antiangiogenic activities. Several studies have indicated that carotenoids used in combination were more effective on antioxidation and anticancer actions than carotenoids used singly. However, it is unclear whether multi-carotenoids have antiangiogenic effects. We investigated the effects of multi-carotenoids at physiological plasma levels of Taiwanese (abbreviated as MCT, with a total of 1.4 µM) and Americans (abbreviated as MCA, with a total of 1.8 µM), and of post-supplemental plasma levels (abbreviated as HMC with a total of 3.55 µM) on vascular endothelial growth factor (VEGF)-induced tube formation in human umbilical vein endothelial cells (HUVECs) and rat aortic rings. MCT, MCA, and HMC inhibited VEGF-induced migration, invasion, and tube formation of HUVECs as well as new vessels formation in rat aortic rings. MCT, MCA, and HMC inhibited activities o\f matrix metalloproteinase (MMP)-2, urokinase plasminogen activator, and phosphorylation of VEGF receptor 2 induced by VEGF. Moreover, MCT, MCA, and HMC significantly upregulated protein expression of tissue inhibitors of MMP-2 and plasminogen activator inhibitor-1. These results demonstrate the antiangiogenic effect of multi-carotenoids both in vitro and ex vivo with possible mechanistic actions involving attenuation of VEGF receptor 2 phosphorylation and extracellular matrix degradation.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Aorta/efectos de los fármacos , Carotenoides/farmacología , Factor A de Crecimiento Endotelial Vascular/farmacología , Animales , Carotenoides/sangre , Movimiento Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Fosforilación/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Ratas Sprague-Dawley , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
6.
Toxicol Appl Pharmacol ; 307: 115-122, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27475717

RESUMEN

Andrographolide, a diterpenoid, is the most abundant terpenoid in Andrographis paniculata, a popular Chinese herbal medicine. Andrographolide displays diverse biological activities including hypoglycemia, hypolipidemia, anti-inflammation, and anti-tumorigenesis. Recent evidence indicates that andrographolide displays anti-obesity property by inhibiting lipogenic gene expression, however, the underlying mechanisms remain to be elucidated. In this study, the effects of andrographolide on transcription factor cascade and mitotic clonal expansion in 3T3-L1 preadipocyte differentiation into adipocyte were determined. Andrographolide dose-dependently (0-15µM) inhibited CCAAT/enhancer-binding protein α (C/EBPα) and C/EBPß mRNA and protein expression as well as peroxisome proliferator-activated receptor γ (PPARγ) protein level during the adipogenesis of 3T3-L1 cells. Concomitantly, fatty acid synthase and stearoyl-CoA desaturase expression and lipid accumulation were attenuated by andrographolide. Oil-red O staining further showed that the first 48h after the initiation of differentiation was critical for andrographolide inhibition of adipocyte formation. Andrographolide inhibited the phosphorylation of PKA and the activation of cAMP response element-binding protein (CREB) in response to a differentiation cocktail, which led to attenuated C/EBPß expression. In addition, ERK and GSK3ß-dependent C/EBPß phosphorylation was attenuated by andrographolide. Moreover, andrographolide suppressed cyclin A, cyclin E, and CDK2 expression and impaired the progression of mitotic clonal expansion (MCE) by arresting the cell cycle at the Go/G1 phase. Taken together, these results indicate that andrographolide has a potent anti-obesity action by inhibiting PKA-CREB-mediated C/EBPß expression as well as C/EBPß transcriptional activity, which halts MCE progression and attenuates C/EBPα and PPARγ expression.


Asunto(s)
Adipogénesis/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Proteína beta Potenciadora de Unión a CCAAT/antagonistas & inhibidores , Diterpenos/farmacología , Células 3T3-L1 , Animales , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ratones , PPAR gamma/metabolismo
7.
Molecules ; 21(12)2016 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-27941649

RESUMEN

Liver cancer is the most endemic cancer in a large region of the world. This study investigated the anti-metastatic effects of an extract of Monascus purpureus CWT715 (MP) fermented from sorghum liquor biowaste and its mechanisms of action in highly metastatic human hepatocarcinoma SK-Hep-1 cells. Kinmen sorghum liquor waste was used as the primary nutrient source to produce metabolites (including pigments) of MP. In the presence of 10 µg/mL MP-fermented broth (MFB), the anti-invasive activity increased with increasing fermentation time reaching a maximum at six days of fermentation. Interestingly, MFB also produced maximal pigment content at six days. Treatment for 24 h with MFB (10-100 µg/mL) obtained from fermentation for six days significantly inhibited cell migration and invasion, and these effects were concentration-dependent. MFB also significantly enhanced nm23-H1 protein expression in a concentration-dependent manner, which was highly correlated with migration and invasion. These results suggest that MFB has significant anti-migration and anti-invasion activities and that these effects are associated with the induction of nm23-H1 protein expression.


Asunto(s)
Monascus/química , Invasividad Neoplásica/prevención & control , Metástasis de la Neoplasia/prevención & control , Extractos Vegetales/farmacología , Sorghum/química , Línea Celular Tumoral , Fermentación , Humanos
8.
Molecules ; 21(11)2016 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-27809254

RESUMEN

The aim of the present study was to determine whether Lactobacillus salivarius (LS) and Lactobacillus johnsonii (LJ) prevent alcoholic liver damage in HepG2 cells and rat models of acute alcohol exposure. In this study, heat-killed LS and LJ were screened from 50 Lactobacillus strains induced by 100 mM alcohol in HepG2 cells. The severity of alcoholic liver injury was determined by measuring the levels of aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (γ-GT), lipid peroxidation, triglyceride (TG) and total cholesterol. Our results indicated that heat-killed LS and LJ reduced AST, ALT, γ-GT and malondialdehyde (MDA) levels and outperformed other bacterial strains in cell line studies. We further evaluated these findings by administering these strains to rats. Only LS was able to reduce serum AST levels, which it did by 26.2%. In addition LS significantly inhibited serum TG levels by 39.2%. However, both strains were unable to inhibit ALT levels. In summary, we demonstrated that heat-killed LS and LJ possess hepatoprotective properties induced by alcohol both in vitro and in vivo.


Asunto(s)
Hepatitis Alcohólica/tratamiento farmacológico , Lactobacillus johnsonii , Ligilactobacillus salivarius , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Colesterol/sangre , Células Hep G2 , Hepatitis Alcohólica/sangre , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangre , gamma-Glutamiltransferasa/sangre
9.
Toxicol Appl Pharmacol ; 280(1): 1-9, 2014 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25110055

RESUMEN

Andrographolide, a bioactive diterpenoid, is identified in Andrographis paniculata. In this study, we investigated the pharmacokinetics and bioavailability of andrographolide in rats and studied whether andrographolide enhances antioxidant defense in a variety of tissues and protects against carbon tetrachloride-induced oxidative damage. After a single 50-mg/kg administration, the maximum plasma concentration of andrographolide was 1µM which peaked at 30min. The bioavailability of andrographolide was 1.19%. In a hepatoprotection study, rats were intragastrically dosed with 30 or 50mg/kg andrographolide for 5 consecutive days. The results showed that andrographolide up-regulated glutamate cysteine ligase (GCL) catalytic and modifier subunits, superoxide dismutase (SOD)-1, heme oxygenase (HO)-1, and glutathione (GSH) S-transferase (GST) Ya/Yb protein and mRNA expression in the liver, heart, and kidneys. The activity of SOD, GST, and GSH reductase was also increased in rats dosed with andrographolide (p<0.05). Immunoblot analysis and EMSA revealed that andrographolide increased nuclear Nrf2 contents and Nrf2 binding to DNA, respectively. After the 5-day andrographolide treatment, one group of animals was intraperitoneally injected with carbon tetrachloride (CCl4) at day 6. Andrographolide pretreatment suppressed CCl4-induced plasma aminotransferase activity and hepatic lipid peroxidation (p<0.05). These results suggest that andrographolide is quickly absorbed in the intestinal tract in rats with a bioavailability of 1.19%. Andrographolide protects against chemical-induced oxidative damage by up-regulating the gene transcription and activity of antioxidant enzymes in various tissues.


Asunto(s)
Antioxidantes/farmacocinética , Tetracloruro de Carbono/toxicidad , Diterpenos/farmacocinética , Estrés Oxidativo/efectos de los fármacos , Animales , Disponibilidad Biológica , Diterpenos/sangre , Masculino , Estrés Oxidativo/fisiología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
10.
Arch Toxicol ; 87(1): 167-78, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22864849

RESUMEN

Chrysin, apigenin, and luteolin are flavones that differ in their number of hydroxyl groups in the B ring. In this study, we investigated the protection by chrysin, apigenin, and luteolin against tert-butyl hydroperoxide (tBHP)-induced oxidative stress and the possible mechanisms involved in rat primary hepatocytes. Chrysin, apigenin, and luteolin dose-dependently up-regulated the protein expression of heme oxygenase 1 (HO-1) and glutamate cysteine ligase (GCL) catalytic (GCLC) and modifier subunit (GCLM) and increased the intracellular glutathione (GSH) content and the ratio of GSH to oxidized GSH. Among the flavones studied, chrysin showed the greatest induction of HO-1, GCLC, and GCLM protein expression and GSH content. Cellular reactive oxygen species production induced by tBHP was attenuated by pretreatment with chrysin, apigenin, and luteolin (P < .05), and this protection was reversed by the GCL inhibitor l-buthionine-S-sulfoximine and the HO-1 inhibitor zinc protoporphyrin. Chrysin, apigenin, and luteolin activated extracellular signal-regulated protein kinase 2 (ERK2), nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, nuclear Nrf2-antioxidant responsive element (ARE) binding activity, and ARE-dependent luciferase activity. Both ERK2 and Nrf2 siRNAs attenuated chrysin-induced HO-1, GCLC, and GCLM protein expression. Taken together, these results suggest that chrysin, apigenin, and luteolin inhibit tBHP-induced oxidative stress by up-regulating HO-1, GCLC, and GCLM gene transcription via the ERK2/Nrf2/ARE signaling pathways in rat primary hepatocytes.


Asunto(s)
Apigenina/farmacología , Flavonoides/farmacología , Glutamato-Cisteína Ligasa/genética , Hemo Oxigenasa (Desciclizante)/genética , Hepatocitos/efectos de los fármacos , Luteolina/farmacología , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Apigenina/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Flavonoides/química , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato-Cisteína Ligasa/metabolismo , Glutatión/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , Hepatocitos/metabolismo , Luteolina/química , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Ratas Sprague-Dawley , Elementos de Respuesta , Regulación hacia Arriba/efectos de los fármacos , terc-Butilhidroperóxido/farmacología
11.
Sci Rep ; 13(1): 4324, 2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36922639

RESUMEN

ß-ionone (ION) is a cyclic terpenoid compound that demonstrates considerable potential for the prevention and treatment of cancer. However, the water solubility of ß-ionone is poor and the compound demonstrates low permeability. Liposomes have been reported as increasing both qualities. In this study, the development of ß-ionone liposomes was initiated by adding 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) to produce cationic liposomes as a means of enhancing binding to cancer cells. Liposomes composed of ß-ionone, HSPC, cholesterol, and DSPE-mPEG2000 were prepared using the thin layer hydration method. Cellular uptake studies were carried out with HeLa cells incubated with ß-ionone liposomes for two hours. The results indicated that the addition of DOTAP increased particle size and affected the spectroscopical and thermogram profiles of the liposomes, thereby confirming reduction in liposome crystallinity, while the zeta potential became positive. Moreover, the calcein release profile further showed that additional DOTAP increased both membrane fluidity and cellular uptake in HeLa cells In conclusion, adding DOTAP affected the physicochemical cationic properties of liposome and improved cellular uptake in HeLa cells.


Asunto(s)
Liposomas , Propano , Humanos , Liposomas/química , Células HeLa , Compuestos de Amonio Cuaternario/farmacología , Compuestos de Amonio Cuaternario/química , Ácidos Grasos Monoinsaturados/química
12.
PLoS One ; 18(9): e0291462, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37699022

RESUMEN

Both quercetin and leucine have been shown to exert moderately beneficial effects in preventing muscle atrophy induced by cancers or chemotherapy. However, the combined effects of quercetin and leucine, as well as the possible underlying mechanisms against cisplatin (CDDP)-induced muscle atrophy and cancer-related fatigue (CRF) remain unclear. To investigate the issues, male BALB/c mice were randomly assigned to the following groups for 9 weeks: Control, CDDP (3 mg/kg/week), CDDP+Q (quercetin 200 mg/kg/day administrated by gavage), CDDP+LL (a diet containing 0.8% leucine), CDDP+Q+LL, CDDP+HL (a diet containing 1.6% leucine), and CDDP+Q+HL. The results showed that quercetin in combination with LL or HL synergistically or additively attenuated CDDP-induced decreases in maximum grip strength, fat and muscle mass, muscle fiber size and MyHC level in muscle tissues. However, the combined effects on locomotor activity were less than additive. The combined treatments decreased the activation of the Akt/FoxO1/atrogin-1/MuRF1 signaling pathway (associated with muscle protein degradation), increased the activation of the mTOR and E2F-1 signaling pathways (associated with muscle protein synthesis and cell cycle/growth, respectively). The combined effects on signaling molecules present in muscle tissues were only additive or less. In addition, only Q+HL significantly increased glycogen levels compared to the CDDP group, while the combined treatments considerably decreased CDDP-induced proinflammatory cytokine and MCP-1 levels in the triceps muscle. Using tumor-bearing mice, we demonstrated that the combined treatments did not decrease the anticancer effect of CDDP. In conclusion, this study suggests that the combination of quercetin and leucine enhanced the suppressed effects on CDDP-induced muscle weakness and CRF through downregulating muscle atrophy and upregulating the glycogen level in muscle tissues without compromising the anticancer effect of CDDP. Multiple mechanisms, including regulation of several signaling pathways and decrease in proinflammatory mediator levels in muscles may contributed to the enhanced protective effect of the combined treatments on muscle atrophy.


Asunto(s)
Cisplatino , Quercetina , Masculino , Animales , Ratones , Quercetina/farmacología , Quercetina/uso terapéutico , Cisplatino/efectos adversos , Leucina/farmacología , Atrofia Muscular/inducido químicamente , Atrofia Muscular/tratamiento farmacológico , Fatiga , Glucógeno
13.
Invest New Drugs ; 30(4): 1449-59, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21826440

RESUMEN

The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synergistic anti-metastatic efficacy of a combination of sorafenib (SF), a multi-kinase inhibitor, and ß-ionone (BI), a precursor of carotenoids. We found that SF (1 µM) in combination with BI (1 µM) synergistically inhibited cell invasion and additively inhibited cell migration, especially at 48 h of incubation. Mechanistically, the combination of SF and BI was found to decrease the protein expression of focal adhesion kinase (FAK) and Rho, and to enhance the protein expression of tissue inhibitor matrix metalloproteinase (TIMP)-1 and TIMP-2. In addition, the combination of SF and BI inhibited the activity of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased the phosphorylation of FAK and of Rac1 proteins. Importantly, SF enhanced the suppressing effect of BI (1-50 µM) on the viability of SK-Hep-1 cells, but not on murine hepatic BNL CL.2 cells, indicating the selective cytotoxicity of this combination on tumor cells. The combination of SF and BI could be a potential therapeutic strategy against human hepatoma cells.


Asunto(s)
Bencenosulfonatos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Norisoprenoides/uso terapéutico , Piridinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/farmacología , Carcinoma Hepatocelular/enzimología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Neoplasias Hepáticas/enzimología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Niacinamida/análogos & derivados , Norisoprenoides/farmacología , Compuestos de Fenilurea , Fosforilación/efectos de los fármacos , Piridinas/farmacología , Sorafenib , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Proteínas de Unión al GTP rho/metabolismo
14.
Br J Nutr ; 107(5): 631-8, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21787455

RESUMEN

ß-Ionone (BI), a precursor for carotenoids, is widely distributed in fruit and vegetables. Recent in vitro studies have demonstrated the potential anti-metastatic effects of BI, but the mechanisms underlying such actions are not clear. Because liver cancer is the most endemic cancer in Taiwan and in a large region of the world, we hereby investigate the anti-metastatic effects of BI and its mechanisms of actions in a highly metastatic human hepatocarcinoma SK-Hep-1 cells. We show that incubation of cells with BI (1-50 µm) for 24 and 48 h significantly inhibited cell invasion, migration and adhesion. Mechanistically, incubation of cells with BI (1-50 µm) for 24 h resulted in the following: (1) significant inhibition of matrix metalloproteinase (MMP)-2, MMP-9 and urokinase-type plasminogen activator activities, (2) up-regulation of protein expression of the tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2 and plasminogen activator inhibitor-1, (3) down-regulation of the expression of migration-related proteins, including focal adhesion kinase (FAK), phosphorylated form of FAK, Rho, Rac1 and Cdc42 and (4) up-regulation of the expression of nm23-H1 protein (P < 0·05). Overall, the results show that BI effectively inhibits the metastasis of SK-Hep-1 cells, and this effect involves the regulation of gene expression and signal pathways related to invasion and migration.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Norisoprenoides/farmacología , Carcinoma Hepatocelular/secundario , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular , Regulación hacia Abajo/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Gelatinasas/metabolismo , Humanos , Nucleósido Difosfato Quinasas NM23/metabolismo , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo
15.
In Vivo ; 35(4): 2141-2149, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34182490

RESUMEN

BACKGROUND/AIM: Oridonin (Ori) is a diterpenoid naturally present in medicinal plants with a potential as an antioxidant agent. This study aimed to evaluate the hepatic anti-oxidative, anti-glycative and anti-inflammatory properties of Ori at 0.125 and 0.25% against chronic ethanol intake in mice. MATERIALS AND METHODS: Mice were divided into five groups: i) normal diet group, ii) Ori group, iii) ethanol diet (Lieber-DeCarli liquid diet with ethanol) group, iv) ethanol diet plus 0.125% Ori and v) ethanol diet plus 0.25% Ori. After 8 weeks of Ori supplementation, blood and liver tissue were used for analyses. RESULTS: Ethanol increased the production of reactive oxygen species and nitric oxide, decreased glutathione content, and lowered the activity of glutathione peroxide, glutathione reductase and catalase. Ethanol suppressed the hepatic mRNA expression of nuclear factor E2-related factor 2. Ori supplements reversed these changes. Ethanol increased hepatic Ne-(carboxyethymethyl)-lysine (CML) and pentosidine levels, and enhanced aldose reductase (AR) activity and mRNA expression. Ori supplements at only 0.25% decreased CML and pentosidine levels, and lowered the AR activity as well as its mRNA expression. Ethanol increased the hepatic release of tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin (IL)-1beta and IL-6. Histological data showed that ethanol induced necrosis and inflammatory cell infiltration, while Ori supplements alleviated these inflammatory responses. Ethanol up-regulated the hepatic mRNA expression of nuclear factor kappa B, myeloperoxidase and p38. Ori supplements reversed these changes. CONCLUSIONS: These novel findings suggest that Ori could be used as a potent agent against alcohol-induced hepatotoxicity.


Asunto(s)
Alcoholismo , Consumo de Bebidas Alcohólicas , Animales , Diterpenos de Tipo Kaurano , Hígado/metabolismo , Ratones , Estrés Oxidativo
16.
Food Chem Toxicol ; 154: 112318, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34116103

RESUMEN

Docosahexaenoic acid (DHA) is known to regulate autophagy in cancer cells. We explored whether oxidative stress-induced growth inhibitor 1 (OSGIN1) is involved in the regulation of autophagy by DHA in breast cancer cells and the possible mechanisms involved. DHA upregulated the levels of OSGIN1, LC3-II and SQSTM1/p62. By contrast, DHA dose-dependently decreased the levels of mTOR and p-mTORS2448 expression. Using GFP/RFP-LC3 fluorescence staining, we showed that cells treated with DHA showed a dose-dependent response in autophagic signals. OSGIN1 Overexpression mimicked DHA treatment in that LC3-II and GFP/RFP-LC3 signals as well as the expression of p-AMPKαT172 and p-RaptorS792 were significantly increased, whereas mTOR, p-mTORS2448, and p-ULK1S757 expression were decreased. With knockdown of OSGIN1 expression, these outcomes were reversed. Moreover, OSGIN1 overexpression transiently elevated the accumulation of OSGIN1 and reactive oxygen species (ROS) in the mitochondrial fraction and subsequently increased p-AMPKαT172 and p-RaptorS792 expression. Upon pretreatment with Mito-TEMPO, a scavenger of mitochondrial ROS, these outcomes were reversed. Taken together, these results suggest that DHA can transiently elevate the generation of ROS in mitochondria and promote autophagosome formation through activation of the p-AMPKαT172/p-Raptor S792 and inactivation of the p-mTORS2448/p-ULK1Ser757 signaling pathways, and these effects depend on OSGIN1 protein in MCF-7 cells.


Asunto(s)
Adenilato Quinasa/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagosomas/metabolismo , Ácidos Docosahexaenoicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Activación Enzimática , Humanos , Células MCF-7 , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal
17.
Am J Chin Med ; 49(6): 1473-1491, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34240660

RESUMEN

14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 [Formula: see text]M dose-dependently activated phosphorylation of AMPK[Formula: see text] and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK[Formula: see text] and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR[Formula: see text]. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK[Formula: see text] and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK[Formula: see text] and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR[Formula: see text]-dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Diterpenos/farmacología , Proteínas Activadoras de GTPasa/metabolismo , Intolerancia a la Glucosa/tratamiento farmacológico , Transportador de Glucosa de Tipo 4/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos
18.
Clin Exp Pharmacol Physiol ; 37(5-6): 605-12, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20082627

RESUMEN

1. The aim of the present study was to investigate the molecular mechanisms by which pipoxolan exerts its inhibitory effects and apoptotic activity in human leukaemia HL-60 cells. 2. The effects of pipoxolan on the proliferation of HL-60 cells and on the distribution of cells within different phases of the cell cycle were investigated indirectly using a Trypan blue assay and a flow cytometer, respectively. The effects of pipoxolan on the apoptosis of HL-60 cells was investigated using DNA fragmentation and flow cytometer. The expression of factors affecting the cell cycle and apoptosis, including p53, p21, Bax, Bcl2, cytochrome c, caspase 3 and caspase 9, was examined by western blotting. 3. At 6.25 microg/mL, pipoxolan significantly induced apoptosis in human leukaemia HL-60 cells after 24 h exposure. In addition, HL-60 cells were arrested in the G(0)/G(1) phase via the induction of p53/p21 by pipoxolan. Apoptosis was associated with an increased Bax/Bcl-2 ratio, cytochrome c release, cleavage of procaspases-9 and -3 and hydrolysis of poly(ADP-ribose) polymerase. Intracellular reactive oxygen species (ROS) seem to play a key role in the pipoxolan-induced apoptosis, because high levels of ROS were produced early in the drug treatment. Apoptosis was significantly abrogated by the free radical scavenger N-acetylcysteine (NAC).


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dioxolanos/farmacología , Fase G1/efectos de los fármacos , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Antineoplásicos/química , Western Blotting , Caspasa 3/metabolismo , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Dioxolanos/química , Citometría de Flujo , Células HL-60 , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo
19.
Nutrients ; 12(2)2020 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-32085637

RESUMEN

14-Deoxy-11,12-didehydroandrographolide (deAND), a diterpenoid in Andrographis paniculata (Burm. f.) Nees, acts as a bioactive phytonutrient that can treat many diseases. To investigate the protective effects of deAND on reducing fatty liver disease, male mice were fed a high-fat and high-cholesterol (HFHC) diet without or with 0.05% and 0.1% deAND supplementation. Cholesterol accumulation, antioxidant, and anti-inflammatory activities in liver and liver injury were evaluated after deAND treatment. The results show that deAND treatment for seven weeks reduced plasma alanine aminotransferase activity and lowered hepatic cholesterol accumulation, tumor nuclear factor-α, and histological lesions. The 0.1% deAND treatment reduced HFHC diet-induced apoptosis by lowering the caspase 3/pro-caspase 3 ratio. After 11 weeks of deAND treatment, increased NOD-like receptor protein 3 (NLRP3), capase-1, and interleukin-1ß protein levels in liver were suppressed by deAND treatment. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, heme oxygenase-1 protein expression, and the activities of glutathione peroxidase and glutathione reductase were increased in mice fed the HFHC diet. However, those activities of antioxidant enzymes or proteins were also upregulated by 0.1% deAND treatment. Furthermore, deAND treatment tended to lower hepatic lipid peroxides. Finally, deAND treatment reversed the depletion of hepatic glutamate level induced by the HFHC diet. These results indicate that deAND may ameliorate HFHC diet-induced steatohepatitis and liver injury by increasing antioxidant and anti-inflammatory activities.


Asunto(s)
Andrographis/química , Colesterol en la Dieta/efectos adversos , Dieta Alta en Grasa/efectos adversos , Diterpenos/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Fitoquímicos/uso terapéutico , Fitoterapia , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/metabolismo , Colesterol/metabolismo , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Ácido Glutámico/metabolismo , Peróxidos Lipídicos/metabolismo , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Fitoquímicos/aislamiento & purificación , Factor de Necrosis Tumoral alfa/metabolismo
20.
J Agric Food Chem ; 68(51): 15228-15238, 2020 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-33301311

RESUMEN

Obesity caused lipotoxicity, which results in insulin resistance. We studied whether benzyl isothiocyanate (BITC) improved insulin resistance in muscle. BITC was studied in vivo in mice fed a high-fat diet (HFD) and in vitro in C2C12 myotubes treated with palmitic acid (PA). In C2C12 cells, BITC mitigated PA inhibition of glucose uptake and phosphorylation of IRS-1, AKT, and TBC1D1 in response to insulin. BITC upregulated the expression of HO-1, GSTP, and GCLM mRNA and protein as well as GSH contents, which suppressed oxidative damage. Knockdown of Nrf2 abrogated BITC enhancement of antioxidant defense and subsequently reversed BITC protection against PA-induced insulin resistance. Moreover, BITC upregulated the expression of GLUT4, PPARγ, and C/EBPα. In HFD-fed mice, plasma total cholesterol, nonesterified fatty acid, and glucose levels and HOMA-IR were dose-dependently decreased with 0.05 or 0.1% BITC administration. In gastrocnemius muscle, compared with the HFD group, BITC increased the phosphorylation of AKT and TBC1D1, GSH contents, and the expression of antioxidant enzymes as well as GLUT4. These results indicate that BITC ameliorates obesity-induced hyperglycemia by enhancing insulin sensitivity in muscle. This is partly attributed to its inhibition of lipotoxicity-induced oxidative insult and upregulation of GLUT4 expression.


Asunto(s)
Proteínas Activadoras de GTPasa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Hiperglucemia/tratamiento farmacológico , Proteínas Sustrato del Receptor de Insulina/metabolismo , Isotiocianatos/administración & dosificación , Músculo Esquelético/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Antioxidantes/metabolismo , Dieta Alta en Grasa/efectos adversos , Proteínas Activadoras de GTPasa/genética , Transportador de Glucosa de Tipo 4/genética , Humanos , Hiperglucemia/etiología , Hiperglucemia/genética , Hiperglucemia/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , PPAR gamma/genética , PPAR gamma/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/efectos de los fármacos
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